Cancellous construct with support ring for repair of osteochondral defects

ABSTRACT

The invention is directed toward an osteochondral repair assembly comprising a shaped allograft construct comprising an unbalanced barbell-shaped cylindrical cancellous bone primary member formed with a mineralized cylindrical base section having a smaller diameter cylindrical stem leading to a second cylindrical section which is demineralized. A mineralized ring-shaped support member is forced over the compressed demineralized second demineralized the aperture of the ring-shaped member to fit around the stem with one ring surface being adjacent the bottom surface to the second cylindrical section and the opposite ring surface being adjacent the upper surface of the mineralized cylindrical base section.

RELATED APPLICATIONS

This application claims the priority of (i) U.S. Provisional PatentApplication Ser. No. 60/904,809 filed Mar. 6, 2007; (ii) U.S.Provisional Patent Application Ser. No. 61/189,252 filed Aug. 15, 2008;and (iii) U.S. Provisional Patent Application Ser. No. 61/205,433 filedJan. 15, 2009. This application is also a continuation-in-partapplication claiming priority to (iv) U.S. patent application Ser. No.12/043,001, filed Mar. 5, 2008; and (v) U.S. patent application Ser. No.12/381,702 filed Mar. 5, 2009. The disclosure of each and everyapplication referenced above is incorporated herein by reference in itsentirety for all purposes.

BACKGROUND OF THE INVENTION

1. Field of Invention

The present invention is generally directed toward an allograft implantconstruct for osteochondral defect repair and is more specificallydirected toward a two piece allograft cancellous bone implant having acancellous bone base member with a mineralized base section, stem anddemineralized top section and a ring-shaped support member which ispulled over the compressed demineralized cancellous top section aroundthe stem. The construct is shaped for an interference fit implantationin a shoulder, knee, hip, or ankle joint, and the construct optionallyfurther contains one or more growth factors impregnated within theconstruct.

2. Description of the Prior Art

Articular cartilage injury and degeneration present medical problems tothe general population which are constantly addressed by orthopedicsurgeons. Every year in the United States, over 500,000 arthroplastic orjoint repair procedures are performed. These include approximately125,000 total hip and 150,000 total knee arthroplasties and over 41,000open arthroscopic procedures to repair cartilaginous defects of theknee.

In the knee joint, the articular cartilage tissue forms a lining whichfaces the joint cavity on one side and is linked to the subchondral boneplate by a narrow layer of calcified cartilage tissue on the other.Articular cartilage (hyaline cartilage) consists primarily ofextracellular matrix with a sparse population of chondrocytesdistributed throughout the tissue. Articular cartilage is composed ofchondrocytes, type II collagen fibril meshwork, proteoglycans, andwater. Active chondrocytes are unique in that they have a relatively lowturnover rate and are sparsely distributed within the surroundingmatrix. The collagens give the tissue its form and tensile strength andthe interaction of proteoglycans with water gives the tissue itsstiffness to compression, resilience and durability. The hyalinecartilage provides a low friction bearing surface over the bony parts ofthe joint. If the lining becomes worn or damaged resulting in lesions,joint movement may be painful or severely restricted. Whereas damagedbone typically can regenerate successfully, hyaline cartilageregeneration is quite limited because of its limited regenerative andreparative abilities.

Articular cartilage lesions generally do not heal, or heal onlypartially under certain biological conditions due to the lack of nerves,blood vessels and a lymphatic system. The limited reparativecapabilities of hyaline cartilage usually results in the generation ofrepair tissue that lacks the structure and biomechanical properties ofnormal cartilage. Generally, the healing of the defect results in afibrocartilaginous repair tissue that lacks the structure and biomedicalproperties of hyaline cartilage and degrades over the course of time.Articular cartilage lesions are frequently associated with disabilityand with symptoms such as joint pain, locking phenomena and reduced ordisturbed function. These lesions are difficult to treat because of thedistinctive structure and function of hyaline cartilage. Such lesionsare believed to progress to severe forms of osteoarthritis.Osteoarthritis is the leading cause of disability and impairment inmiddle-aged and older individuals, entailing significant economic,social and psychological costs. Each year, osteoarthritis accounts foras many as 39 million physician visits and more than 500,000hospitalizations. By the year 2020, arthritis is expected to affectalmost 60 million persons in the United States and to limit the activityof 11.6 million persons.

There are many current therapeutic methods being used. None of thesetherapies has resulted in the successful regeneration of hyaline-liketissue that withstands normal joint loading and activity over prolongedperiods. Currently, the techniques most widely utilized clinically forcartilage defects and degeneration are not articular cartilagesubstitution procedures, but rather lavage, arthroscopic debridement,and repair stimulation. The direct transplantation of cells or tissueinto a defect and the replacement of the defect with biologic orsynthetic substitutions presently accounts for only a small percentageof surgical interventions. The optimum surgical goal is to replace thedefects with cartilage-like substitutes so as to provide pain relief,reduce effusions and inflammation, restore function, reduce disabilityand postpone or alleviate the need for prosthetic replacement.

Lavage and arthroscopic debridement involve irrigation of the joint withsolutions of sodium chloride, Ringer or Ringer and lactate. Thetemporary pain relief is believed to result from removing degenerativecartilage debris, proteolytic enzymes and inflammatory mediators. Thesetechniques provide temporary pain relief, but have little or nopotential for further healing.

Repair stimulation is conducted by means of drilling, abrasionarthroplasty or microfracture. Penetration into the subchondral boneinduces bleeding and fibrin clot formation which promotes initialrepair, however, the tissue formed is fibrous in nature and not durable.Pain relief is temporary as the tissue exhibits degeneration, loss ofresilience, stiffness and wear characteristics over time.

The periosteum and perichondrium have been shown to contain mesenchymalprogenitor cells capable of differentiation and proliferation. They havebeen used as grafts in both animal and human models to repair articulardefects. Few patients over 40 years of age obtain good clinical results,which most likely reflect the decreasing population of osteochondralprogenitor cells with increasing age. There have also been problems withadhesion and stability of the grafts, which result in their displacementor loss from the repair site.

Transplantation of cells grown in culture provides another method ofintroducing a new cell population into chondral and osteochondraldefects. CARTICEL7 is a commercial process to culture a patient's owncartilage cells for use in the repair of cartilage defects in thefemoral condyle marketed by Genzyme Biosurgery in the United States andEurope. The procedure uses arthroscopy to take a biopsy from a healthy,less loaded area of articular cartilage. Enzymatic digestion of theharvested tissue releases the cells that are sent to a laboratory wherethey are grown for a period ranging from 2-5 weeks. Once cultivated, thecells are injected during a more open and extensive knee procedure intoareas of defective cartilage where it is hoped that they will facilitatethe repair of damaged tissue. An autologous periosteal flap with acambium layer is used to seal the transplanted cells in place and act asa mechanical barrier. Fibrin glue is used to seal the edges of the flap.This technique preserves the subchondral bone plate and has reported ahigh success rate. Proponents of this procedure report that it producessatisfactory results, including the ability to return to demandingphysical activities, in more than 90% of patients and those biopsyspecimens of the tissue in the graft sites show hyaline-like cartilagerepair. More work is needed to assess the function and durability of thenew tissue and determine whether it improves joint function and delaysor prevents joint degeneration. As with the perichondrial graft,patient/donor age may compromise the success of this procedure aschondrocyte population decreases with increasing age. Disadvantages tothis procedure include the need for two separate surgical procedures,potential damage to surrounding cartilage when the periosteal patch issutured in place, the requirement of demanding microsurgical techniques,and the expensive cost of the procedure resulting from the cellcultivation which is currently not covered by insurance.

Osteochondral transplantation or mosaicplasty involves excising allinjured or unstable tissue from the articular defect and creatingcylindrical holes in the base of the defect and underlying bone. Theseholes are filled with autologous cylindrical plugs of healthy cartilageand bone in a mosaic fashion. The filler osteochondral plugs areharvested from a lower weight-bearing area of lesser importance in thesame joint. This technique, shown in Prior Art FIG. 2, can be performedas arthroscopic or open procedures. Reports of results of osteochondralplug autografts in a small number of patients indicate that theydecrease pain and improve joint function, however, long-term resultshave not been reported. Factors that can compromise the results includedonor site morbidity, effects of joint incongruity on the opposingsurface of the donor site, damage to the chondrocytes at the articularmargins of the donor and recipient sites during preparation andimplantation, and collapse or settling of the graft over time. Thelimited availability of sites for harvest of osteochondral autograftsrestricts the use of this approach to treatment of relatively smallarticular defects and the healing of the chondral portion of theautograft to the adjacent articular cartilage remains a concern.

Transplantation of large allografts of bone and overlying articularcartilage is another treatment option that involves a greater area thanis suitable for autologous cylindrical plugs, as well as for anon-contained defect. The advantages of osteochondral allografts are thepotential to restore the anatomic contour of the joint, lack ofmorbidity related to graft harvesting, greater availability thanautografts and the ability to prepare allografts in any size toreconstruct, large defects. Clinical experience with fresh and frozenosteochondral allografts shows that these grafts can decrease jointpain, and that the osseous portion of an allograft can heal to the hostbone and the chondral portion can function as an articular surface.Drawbacks associated with this methodology in the clinical situationinclude the scarcity of fresh donor material and problems connected withthe handling and storage of frozen tissue. Fresh allografts carry therisk of immune response or disease transmission. MusculoskeletalTransplant Foundation (MTF) has preserved fresh allografts in a mediathat maintains a cell viability of 50% for 35 days for use as implants.Frozen allografts lack cell viability and have shown a decreased amountof proteoglycan content which contribute to deterioration of the tissue.

A number of United States Patents have been specifically directedtowards bone plugs which are implanted into a bone defect. Examples ofsuch bone plugs are U.S. Pat. No. 4,950,296 issued Aug. 21, 1990 whichdiscloses a bone graft device comprising a cortical shell having aselected outer shape and a cavity formed therein for receiving acancellous plug, which is fitted into the cavity in a manner to exposeat least one surface; U.S. Pat. No. 6,039,762 issued Mar. 21, 2000discloses a cylindrical shell with an interior body of deactivated bonematerial and U.S. Pat. No. 6,398,811 issued Jun. 4, 2002 directed towarda bone spacer which has a cylindrical cortical bone plug with aninternal through going bore designed to hold a reinforcing member. U.S.Pat. No. 6,383,211 issued May 7, 2002 discloses an invertebral implanthaving a substantially cylindrical body with a through going boredimensioned to receive bone growth materials.

U.S. Pat. No. 6,379,385 issued Apr. 30, 2002 discloses an implant basebody of spongious bone material into which a load carrying supportelement is embedded. The support element can take the shape of adiagonal cross or a plurality of cylindrical pins. See also, U.S. Pat.No. 6,294,187 issued Sep. 25, 2001 which is directed to a load bearingosteoimplant made of compressed bone particles in the form of acylinder. The cylinder is provided with a plurality of through goingbores to promote blood flow through the osteoimplant or to hold ademineralized bone and glycerol paste mixture. U.S. Pat. No. 6,096,081issued Aug. 1, 2000 shows a bone dowel with a cortical end cap or capsat both ends, a brittle cancellous body and a through going bore.

The use of implants for cartilage defects is much more limited. Asidefrom the fresh allograft implants and autologous implants, U.S. Pat. No.6,110,209 issued Nov. 5, 1998 shows the use of an autologous articularcartilage cancellous bone paste to fill arthritic defects. The surgicaltechnique is arthroscopic and includes debriding (shaving away loose orfragmented articular cartilage), followed by morselizing the base of thearthritic defect with an awl until bleeding occurs. An osteochondralgraft is then harvested from the inner rim of the intercondylar notchusing a trephine. The graft is then morselized in a bone graft crusher,mixing the articular cartilage with the cancellous bone. The paste isthen pushed into the defect and secured by the adhesive properties ofthe bleeding bone. The paste can also be mixed with a cartilage growthfactor, a plurality of cells, or a biological glue. All patients arekept non-weight bearing for four weeks and use a continuous passivemotion machine for six hours each night. Histologic appearance of thebiopsies has mainly shown a mixture of fibrocartilage with hyalinecartilage. Concerns associated with this method are harvest sitemorbidity and availability, similar to the mosaicplasty method.

U.S. Pat. No. 6,379,367 issued Apr. 30, 2002 discloses a plug with abase membrane, a control plug, and a top membrane which overlies thesurface of the cartilage covering the defective area of the joint.

SUMMARY OF THE INVENTION

In one embodiment, an osteochondral repair allograft construct implantis formed as an unbalanced barbell-shaped cylindrical cancellous bonebase member having a mineralized cylindrical base section and a smallerdiameter cylindrical stem extending there from leading to a secondcylindrical section which is demineralized. In another embodiment, aring shaped support member is forced over the compressed demineralizedsecond cylindrical section and the aperture of the ring member fitsaround the stem with a top surface being adjacent the bottom surface ofthe demineralized cylindrical section and bottom surface being adjacentthe upper surface of the mineralized cylindrical base section.

In another embodiment, the allograft construct implant is used to repairosteochondral defects and is placed in a bore which has been cut intothe patient to remove the lesion defect area. In another embodiment,each osteochondral repair allograft construct implant can support theaddition of a variety of growth factors. In another embodiment, theallograft construct implant can support the addition of a variety ofchondrogenic (in any portion of the construct) and/or osteogenic (in anyportion of the construct save the demineralized top section) growthfactors including, but not limited to morselized allogeneic cartilage,growth factors and variants thereof (FGF-2, FGF-5, FGF-7, FGF-9, FGF-11,FGF-21, IGF-1, TGF-β, TGF-β1, BMP-2, BMP-7, PDGF, VEGF), human allogenicor autologous chondrocytes, human allogenic or autologous bone marrowcells, stem cells, demineralized bone matrix, insulin, insulin-likegrowth factor-1, transforming growth factor-B, interleukin-1 receptorantagonist,. hepatocyte growth factor, platelet-derived growth factor,Indian hedgehog and parathyroid hormone-related peptide or bioactiveglue. These chondrogrenic and/or osteogenic growth factors or additivescan be added throughout the implant or to specific regions of theimplant such as the demineralized top section or the mineralized baseportion, depending on whether chondrogenesis (any portion of theimplant) or osteogenesis (any portion of the implant save thedemineralized top section) is the desired outcome.

In another embodiment, the invention provides an allograft implant forjoints which provides pain relief, restores normal function and willpostpone or alleviate the need for prosthetic replacement.

In another embodiment, the invention provides an osteochondral repairimplant which is easily placed in a defect area by the surgeon using anarthroscopic, minimally invasive technique.

In another embodiment, the invention provides an osteochondral repairimplant which has load bearing capabilities.

In another embodiment, the invention provides an osteochondral repairprocedure which is applicable for both partial and full thicknesscartilage lesions that may or may not be associated with damage to theunderlying bone.

In another embodiment, the invention provides an implant capable offacilitating bone healing and/or repair of hyaline cartilage.

In another embodiment, the invention provides a cancellous constructwhich is simultaneously treated with chondrogenic (in any portion of theimplant) and/or osteogenic (in any portion of the implant save thedemineralized top section) growth factors.

In another embodiment, the invention provides a cancellous constructwhich is treated with chondrogenic growth factors in the portion of theconstruct aimed to repair articular cartilage.

In another embodiment, the invention provides a cancellous constructwhich is treated with chondrogenic growth factors at any portion of theconstruct.

In another embodiment, the invention provides a cancellous constructwhich is treated with osteogenic growth factors in any portion of theconstruct except for the demineralized top portion of the construct.

These and other objects, advantages, and novel features of the presentinvention will become apparent when considered with the teachingscontained in the detailed disclosure along with the accompanyingdrawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the anatomy of a knee joint;

FIG. 2 shows a schematic mosaicplasty as known in the prior art;

FIG. 3 shows an assembled perspective view of the inventive cartilagerepair construct;

FIG. 4 shows a perspective view of the base member of the construct withan unbalanced barbell configuration;

FIG. 5 shows a perspective view of the ring shaped support member of theconstruct;

FIG. 6 is a side elevation view of the assembled construct; and

FIG. 7 shows a cross section view of the construct of FIG. 6 taken alongline 7′-7′.

DESCRIPTION OF THE INVENTION

The term “tissue” is used in the general sense herein to mean anytransplantable or implantable tissue, the survivability of which isimproved by the methods described herein upon implantation. Inparticular, the overall durability and longevity of the implant areimproved, and host-immune system mediated responses, are substantiallyeliminated.

The terms “transplant” and “implant” are used interchangeably to referto tissue, material or cells (xenogeneic or allogeneic) which may beintroduced into the body of a patient.

The terms “autologous” and “autograft” refer to tissue or cells whichoriginate with or are derived from the recipient, whereas the terms“allogeneic” and “allograft” refer to cells or tissue which originatewith or are derived from a donor of the same species as the recipient.

The terms “xenogeneic” and “xenograft” refer to cells or tissue whichoriginate with or are derived from a species other than that of therecipient.

The term “growth factor” means a naturally occurring or syntheticcompound capable of stimulating cellular proliferation and/or cellulardifferentiation. Growth factors are important for regulating a varietyof cellular processes.

The term “ELISA” or “Enzyme-Linked ImmunoSorbent Assay” means abiochemical technique used mainly in immunology to detect the presenceof an antibody or an antigen in a sample. The ELISA has been used as adiagnostic tool in medicine and plant pathology, as well as a qualitycontrol check in various industries. In simple terms, in ELISA anunknown amount of antigen is affixed to a surface, and then a specificantibody is washed over the surface so that it can bind to the antigen.This antibody is linked to an enzyme, and in the final step a substanceis added that the enzyme can convert to some detectable signal. Thus inthe case of fluorescence ELISA, when light is shone upon the sample, anyantigen/antibody complexes will fluoresce so that the amount of antigenin the sample can be measured.

Construct

The present invention is directed towards an osteochondral repairconstruct constructed of cancellous bone taken from allogenic orxenogenic bone sources.

The construct is preferably derived from dense allograft cancellous bonethat may originate from proximal or distal femur, proximal or distaltibia, proximal humerus, talus, calcaneus, patella, or ilium. Cancelloustissue is first processed into blocks and then milled into the desiredshapes such as a cylinder for this present invention. In a preferredembodiment, a barbell-shaped assembly 10 is milled using a lathe on acancellous bone cylinder to form an unbalanced primary base member 12with a top section 14, a cylindrical stem section 16 and a cylindricalbase section 18. The top section 14 is milled to have a thicknesssimilar to the thickness of human articular cartilage (e.g., 1.5-3.5 mm)and the diameter of the implant may vary between 5-25 mm. The stemsection 16 has a diameter approximately half of the diameter of theentire assembly. The base section 18 has a thickness or length which ispreferably larger than the thickness or length of the top section 14with a ratio preferably ranging from of at least about 1.5 to 1 to about6:1. During tissue processing, the top section 14 is substantiallydemineralized by immersing it in dilute acid while the base section 18remains mineralized.

A mineralized cancellous bone ring shaped secondary member 20 has anaperture 22 with a diameter equal to or slightly greater than thediameter of the stem 16 and an outer diameter which is the same as thediameter of the top section 14 and base section 18. However, if desired,the aperture 22 can be 10% to 40% larger than the diameter of the stem16. The top surface 24 and bottom surface 26 of the ring shaped member20 are preferably planar and after assembly the bottom surface 26 isadjacent the top surface 19 of the base section 18 and the top surface24 is adjacent the bottom surface 15 of the top section 14. While thering member 20 is preferably constructed of mineralized allograftcancellous bone, it can be constructed of allograft cortical bone orxenograft bone as long as the same have been decellularized.Alternately, the ring member 20 may be constructed of ceramics orbiocompatible polymers.

Demineralization

The top section 14 is substantially demineralized in dilute acid up to apredetermined level (as indicated by broken-line representation L1 inFIG. 7) until the bone contains less than 0.5% wt/wt residual calcium.Subsequently, the resultant tissue form is predominantly Type Icollagen, which is sponge-like in nature with an elastic quality.Following decalcification, the tissue is further cleaned, brought to aphysiological pH level of about 7 and may also be treated so that thecancellous tissue is non-osteoinductive. This inactivation of inherentosteoinductivity may be accomplished via chemical or thermal treatmentor by high energy irradiation. The cancellous top section 14 ispreferably treated with an oxidizing agent such as hydrogen peroxide inorder to render it non-osteoinductive.

Following demineralization the top section 14 is spongy and deformableallowing it to be squeezed through the center aperture 22 of the ringmember 20. After the implant has been assembled, morselized cartilageparticles combined with a carrier or growth factor may be added to thetop section 14. If desired, the open cancellous structure of the topsection 14 may be loaded with a cartilage paste or gel as noted belowand/or one or more additives namely recombinant or native or variantgrowth factors (FGF-2, FGF-5, FGF-7, FGF-9, FGF-11, FGF-21, IGF-1,TGF-β1, BMP-2, BMP-4, BMP-7, PDGF, VEGF), human allogenic or autologouschondrocytes, human allogenic cells, human allogenic or autologous bonemarrow cells, human allogenic or autologous stem cells, demineralizedbone matrix, insulin, insulin-like growth factor-1, interleukin-1receptor antagonist, hepatocyte growth factor, platelet-derived growthfactor, Indian hedgehog, parathyroid hormone-related peptide, viralvectors for growth factor or DNA delivery, nanoparticles, orplatelet-rich plasma. This design enables the fabrication of an implantthat possesses a relatively uniform substantially demineralized topsection that is distinct from the mineralized base section.

Incorporation of Additives into the Construct

The demineralized portion of the construct can be provided with a matrixof cartilage putty or gel consisting of minced or milled allograftcartilage which has been lyophilized so that its water content rangesfrom about 0.1% to about 8.0% ranging from about 25% to about 50% byweight, mixed with a carrier of sodium hyaluronate solution (HA)(molecular weight ranging from about 7.0×10⁵ to about 1.2×10⁶) or anyother bioabsorbable carrier such as hyaluronic acid and its derivatives,gelatin, collagen, chitosan, alginate, buffered PBS, Dextran CMC, orother polymers, the carrier ranging from about 75% to about 25% byweight. In one embodiment, the cartilage is minced or milled to a sizeless than or equal to about 212 μm. In another embodiment, the cartilageis minced or milled to a size of from about 5 μm to about 212 μm. Inanother embodiment, the cartilage is minced or milled to a size of fromabout 6 μm to about 10 μm. In another embodiment, the cartilage can beminced or milled to a size of less than or equal to about 5 μm. Thesmall size of the minced or milled particulate cartilage can facilitateincreased exposure or release of various growth factors due to theincreased aggregate surface area of the particulate cartilage used.

The cartilage particles can contain endogenous growth factors. Theseendogenous growth factors can be extracted from the cartilage particlesby the method outlined in Example 1 and detected by the method outlinedin Example 2. Exogenous growth factors can also be combined with thecartilage particulate. In one embodiment, cartilage is recovered fromdeceased human donors, and the tissue may be treated with any knownmethod or methods for chemically cleaning or treating a soft tissue. Thecartilage is then lyophilized, milled, then sieved to yield particlesizes of, on average, less than or equal to 212 microns. The cartilageparticles are mixed with a growth factor in an aqueous vehicle, then theparticles can either be lyophilized and stored dry at room temperatureor frozen, or used immediately. For example, particles containingchondrogenic growth factor can be added to any portion of the allograftconstruct, and particles containing osteogenic growth factor can beadded to any portion of the allograft construct save the demineralizedcancellous cap. The mixture containing the cartilage particles andgrowth factor can be lyophilized for storage.

The growth factor can be any one of a variety of growth factors known topromote wound healing, cartilage andior bone development (e.g. BMP'spartictularly BMP-2, FGF's particularly FGF-2 and-9 and/or variants ofFGF-2, IGF, VEGF, PDGF, etc.). The vehicle used to solubilize the growthfactor and adsorb it into the cartilage particles can be saline, water,PBS, Ringers, etc.

In one embodiment, the resulting enhanced cartilage particles cancontain levels of growth factors that are greater than that found inintact cartilage. In another embodiment, the cartilage particle mixturecan be infused into all or part of the construct. If desired, thecartilage particle mixture can be infused primarily into thedemineralized end of the primary member of the construct.

It is further envisioned that cells which have been collected from thepatient or grown outside the patient can be inserted into the entireconstruct or into the cancellous demineralized top section 14 matrixbefore, during or after deposit of the construct 10 into the defectarea. Such cells include, for example, allogenic or autologous bonemarrow cells, stem cells and chondrocyte cells. The cellular density ofthe cells preferably ranges from 1.0×10⁸ to 5.0×10⁸ or from about 100million to about 500 million cells per cc of putty or gel mixture.

Placement of Construct

The construct 10 is placed in an osteochondral defect area bore whichhas been cut in the lesion area of a patient with the upper surface 17of the top section 14 being slightly proud (i.e., above), slightlybelow, or substantially flush with the surface of the original cartilagesurrounding the defect area remaining at the site being treated. Theconstruct 10 has a length which can be the same as the depth of thedefect or more or less than the depth of the bore. If the construct 10is the same as the depth of the bore, the base of the implant issupported by the bottom surface of the bore and the top surface 17 issubstantially level with the articular cartilage. If the construct 10 isof a lesser length, the base of the construct is not supported butsupport is provided by the wall of the defect area bore or respectivecut out area as the plug is interference fit within the bore or cut outarea with the cap being slightly proud, slightly below, or flush withthe surrounding articular cartilage depending on the surgeon'spreference. With such load bearing support, the graft surface is notdamaged by weight or bearing loads which can cause micromotioninterfering with the graft interface producing fibrous tissue interfacesand subchondral cysts.

In operation, the lesion or defect is removed by cutting a blind boreremoving a lesion in the implant area. The construct 10 is then placedin the bore or cut away area in an interface fit with the surroundingwalls.

If the construct is moveable within the bore, suitable organic gluematerial can be used to keep the implant fixed in place in the implantarea. Suitable organic glue material can also be used to keep theadditives in the construct within the construct following implantationinto the defect site. Suitable organic glue material can be foundcommercially, such as for example: TISSEEL 7 or TISSUCOL 7 (fibrin basedadhesive; Immuno AG, Austria), Adhesive Protein (Sigma Chemical, USA),Dow Corning Medical Adhesive B (Dow Corning, USA), fibrinogen thrombin,elastin, collagen, casein, albumin, keratin and the like.

EXAMPLES Example 1 Processed Cartilage Particle Extraction

Cartilage is recovered from deceased human donors, and the tissue may betreated with any known method or methods for chemically cleaning ortreating a soft tissue. The cartilage is then lyophilized,freeze-milled, then sieved to yield particle sizes of, on average, lessthan or equal to 212 microns,. The cartilage particles are -againlyophilized prior to storage or extraction. The particles are extractedin guanidine HCl by incubating at 4° C. on an orbital shaker at 60 rpmfor 24 hr, followed by dialysis (8 k MWCO membrane dialysis tube) in0.05M Tris HCl for 15 hrs at 4° C. The dialysis solution was thenreplaced and the dialysis continued for another 8 hrs at 4° C. Thepost-dialysis extracts were stored at −70° C. until ELISA analysis.

Example 2 Quantification Of Endogenous Growth Factors Present InProcessed Cartilage

0.25 g of cartilage particles were weighed out for each donor. Thecartilage particles were transferred to tubes containing 5 ml ofextraction solution (4M Guanidine HCl in TrisHCl). The cartilageparticles were incubated at 4° C. on the orbital shaker at 60 rpm for 24hr, followed by dialysis (8 k MWCO membrane dialysis tube) in 0.05MTrisHCl for 15 hrs at 4° C. The dialysis solution was then replaced andthe dialysis continued for another 8 hrs at 4° C. The post-dialysisextracts were stored at −70° C. until ELISA run. Notably, the aboveprotocol can also be utilized in order to determine the total growthfactor concentration (e.g., exogenous plus endogenous) present in adevice of the instant invention. TABLE 1 demonstrates the relativeconcentration of endogenous TGF-β1 found in cartilage particles of thepresent invention manufactured in accordance with Example 1 and derivedfrom various subjects.

TABLE 2 demonstrates the relative concentration of endogenous FGF-2found in cartilage particles of the present invention manufactured inaccordance with Example 1 of the present invention and derived fromvarious subjects.

TABLE 3 demonstrates the relative concentration of endogenous BMP-2found in cartilage particles of the present invention manufactured inaccordance with Example 1 of the present invention and derived fromvarious subjects.

The results shown above in TABLES 1-3 indicate that processed cartilageparticles prepared in accordance with the method of Example 1 retain aconcentration of endogenous TGF-β1. The results shown above in TABLES1-3 further indicate that processed cartilage particles prepared inaccordance with the method of Example 1 also retain concentrations ofendogenous BMP-2; and of endogenous FGF-2.

The principles, preferred embodiments and modes of operation of thepresent invention have been described in the foregoing specification.However, the invention should not be construed as limited to theparticular embodiments which have been described above. Instead, theembodiments described here should be regarded as illustrative ratherthan restrictive. Variations and changes may be made by others withoutdeparting from the scope of the present invention as defined by thefollowing claims.

1. A construct for repairing an osteochondral defect, comprising a basemember derived from bone, said base member having a first section, whichis mineralized, and a second section, which has a substantiallydemineralized region, said first and second sections being connected bya stem section; and a ring-shaped member mounted around said stemsection of said base member.
 2. An osteochondral repair construct asrecited in claim 1, wherein each of said first and second sections has acylindrical shape; and wherein said ring-shaped member has a cylindricalshape.
 3. An osteochondral repair construct as recited in claim 2,wherein said first and second sections and said stem section are formedintegrally with each other, whereby said base member has a monolithicconstruction.
 4. An osteochondral repair construct as recited in claim3, wherein each of said first and second sections has a first diameter;and wherein said stem section has a second diameter, which is smallerthan said first diameter.
 5. An osteochondral repair construct asrecited in claim 4, wherein said first and second sections are locatedat opposite ends of said base member; and wherein said stem section islocated intermediate said opposite ends of said base member, wherebysaid base member has a barbell-like shape.
 6. An osteochondral repairconstruct as recited in claim 5, wherein said first section has a firstthickness; and wherein said second section has a second thickness, whichis less than said first thickness.
 7. An osteochondral repair constructas recited in claim 1, wherein said second section of said base memberis demineralized so as to have a residual calcium content not greaterthan about 0.5% wt/wt.
 8. An osteochondral repair construct as recitedin claim 1, wherein said stem section of said base member is at leastpartially demineralized.
 9. An osteochondral repair construct as recitedin claim 1, wherein said ring-shaped member is formed from allograftcancellous or cortical bone.
 10. An osteochondral repair construct asrecited in claim 1, wherein said ring-shaped member is formed fromxenograft cancellous or cortical bone.
 11. An osteochondral repairconstruct as recited in claim 1, wherein said demineralized region ofsaid second section of said base member is treated to benon-osteoinductive.
 12. An osteochondral repair construct as recited inclaim 1, wherein said base member is formed from allograft cancellousbone.
 13. An osteochondral repair construct as recited in claim 1,wherein said base member is formed from xenograft cancellous bone. 14.An osteochondral repair construct as recited in claim 1, wherein saidstem section has a first diameter; and wherein said ring member includesan aperture having a second diameter, which is similar to said firstdiameter of said stem section.
 15. An osteochondral repair construct asrecited in claim 14, wherein said second diameter of said ring-shapedmember is larger than said first diameter of said stem section by about10% to about 40%.
 16. An osteochondral repair construct as recited inclaim 1, wherein said ring-shaped member is constructed of materialstaken from a group consisting of allograft bone, xenograft bone,ceramics and biocompatible plastic polymers.
 17. An osteochondral repairconstruct as recited in claim 1, wherein said second section of saidbase member contains cartilage particles.
 18. An osteochondral repairconstruct as recited in claim 1, wherein said second section of saidbase member contains cartilage particles mixed in a biocompatiblecarrier.
 19. An osteochondral repair construct as recited in claim 18,wherein said cartilage particles are derived from allograft or autograftcartilage.
 20. An osteochondral repair construct as recited in claim 18,wherein said cartilage particles contain endogenous growth factors. 21.An osteochondral repair construct as recited in claim 20, wherein saidendogenous growth factor is TGF-β1.
 22. An osteochondral repairconstruct as recited in claim 20, wherein said endogenous growth factoris FGF-2.
 23. An osteochondral repair construct as recited in claim 20,wherein said endogenous growth factor is BMP-2.
 24. An osteochondralrepair construct as recited in claim 18, wherein said cartilageparticles contain at least one additive taken from a group consisting ofand variants thereof (FGF-2, FGF-5, FGF-7, FGF-9, FGF-11, FGF-21, IGF-1,TGF-β, TGF-β1, BMP-2, BMP-4, BMP-7, PDGF, VEGF), human allogeneic orautologous chondrocytes, human allogeneic or autologous bone marrowcells, stem cells, insulin, insulin-like growth factor-1, transforminggrowth factor-B, interleukin-1 receptor antagonist, hepatocyte growthfactor, platelet-derived growth factor, Indian hedgehog and parathyroidhormone-related peptide, bioactive glue, viral vectors for growth factoror DNA delivery, nanoparticles, or platelet-rich plasma.
 25. Anosteochondral repair construct as recited in claim 18, wherein saidcartilage particles contain at least one additive taken from a groupconsisting of growth factors and variants of FGF-2, FGF-5, FGF-7, FGF-9,FGF-11 and FGF-21.
 26. An osteochondral repair construct as recited inclaim 18, wherein said cartilage particles are milled.
 27. Anosteochondral repair construct as recited in claim 18, wherein saidcartilage particles are morselized.
 28. An osteochondral construct asrecited in claim 1, wherein at least one of said base member and saidring-shaped member contains at least one additive taken from a groupconsisting of growth factors and variants thereof (FGF-2, FGF-5, FGF-7,FGF-9, FGF-11, FGF-21, IGF-1, TGF-β, TGF-β1, BMP-2, BMP4, BMP-7, PDGF,VEGF), human allogeneic or autologous chondrocytes, human allogeneic orautologous bone marrow cells, stem cells, demineralized bone matrix,allograft or autograft cartilage particles, insulin, insulin-like growthfactor-1, transforming growth factor-B, interleukin-1 receptorantagonist, hepatocyte growth factor, platelet-derived growth factor,Indian hedgehog and parathyroid hormone-related peptide, bioactive glue,viral vectors for growth factor or DNA delivery, nanoparticles, orplatelet-rich plasma.
 29. An osteochondral construct as recited in claim1, wherein said second section of said base member contains at least oneadditive taken from a group consisting of growth factors and variantsthereof (FGF-2, FGF-5, FGF-7, FGF-9, FGF-11, FGF-21, IGF-1, TGF-b,TGF-B1, BMP-2, BMP-4, BMP-7, PDGF, VEGF), human allogeneic or autologouschondrocytes, human allogeneic or autologous bone marrow cells, stemcells, demineralized bone matrix, allograft or autograft cartilageparticles, insulin, insulin-like growth factor-1, transforming growthfactor-B, interleukin-1 receptor antagonist, hepatocyte growth factor,platelet-derived growth factor, Indian hedgehog and parathyroidhormone-related peptide, bioactive glue, viral vectors for growth factoror DNA delivery, nanoparticles, or platelet-rich plasma.
 30. Anosteochondral construct as recited in claim 1, wherein said secondsection of said base member contains at least one chondrogenic additiveand said first section of said base member contains at least oneosteogenic additive.
 31. An osteochondral construct as recited in claim1, wherein said second section of said base member contains at least onechondrogenic additive; wherein said first section of said base membercontains at least one osteogenic additive; and wherein said ring-shapedmember contains at least one osteogenic additive.
 32. An osteochondralrepair construct as recited in claim 1, wherein said second section ofsaid base member contains at least one additive taken from a groupconsisting of growth factors and variants of FGF-2, FGF-5, FGF-7, FGF-9,FGF-11 and FGF-21.
 33. A process for assembling an osteochondral repairconstruct having a base member, which includes a stem sectionintermediate opposite ends of said base member, and a ring-shapedmember, which is mountable on said stem section, said method comprisingthe steps of: a. demineralizing one of said ends of said base membersuch that said one end is compressible; b. compressing said one end ofsaid base member; c. inserting said ring-shaped member over said one endof said base member while said one end is compressed; and d. locatingsaid ring-shaped member around said stem section of said base member.34. The process recited in claim 33, further comprising the steps of e.providing cartilage particles mixed in a biocompatible carrier to form acartilage particle mixture; and f. incorporating said cartilage particlemixture into said one end of said base member.